Summary of study ST001241

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000830. The data can be accessed directly via it's Project DOI: 10.21228/M8D68Q This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST001241
Study TitleGlobal Metabolic Analysis Trisomy 21 - Cohort 3, Plasma
Study SummaryGlobal metabolic analysis of plasma from individuals with and without trisomy 21.
Institute
University of Colorado, Denver
Last NameCulp-Hill
First NameRachel
Address12801 E 17th Ave L18-9403D, Aurora, Colorado, 80045, USA
Emailrachel.hill@cuanschutz.edu
Phone303-724-5798
Submit Date2019-08-13
Raw Data AvailableYes
Raw Data File Type(s).raw
Analysis Type DetailLC-MS
Release Date2019-08-21
Release Version1
Rachel Culp-Hill Rachel Culp-Hill
https://dx.doi.org/10.21228/M8D68Q
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000830
Project DOI:doi: 10.21228/M8D68Q
Project Title:Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
Project Summary:Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by unknown mechanisms. We report here a large metabolomics study of plasma and cerebrospinal fluid showing that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. We demonstrate that immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, we show positive correlations among levels of IFN-inducible cytokines and KP dysregulation. Using metabolic tracing assays, we determine that IFN stimulation causes IDO1 overexpression and kynurenine overproduction in cells with T21, dependent on overexpression of IFN receptors encoded on chromosome 21. Finally, we show a mouse model of DS carrying triplication of the IFN receptors exhibits KP dysregulation. Altogether, these results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.
Institute:University of Colorado, Denver
Laboratory:Linda Crnic Institute, Costello Lab, D'Alessandro Lab
Last Name:Culp-Hill
First Name:Rachel
Address:12801 E 17th Ave L18-9403D, Aurora, Colorado, 80045, USA
Email:rachel.hill@cuanschutz.edu
Phone:303-724-5798

Subject:

Subject ID:SU001309
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Age Or Age Range:0.5 - 76.5
Gender:Male and female

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Cohort
SA090110nHTP_5neg_D21_1-70-6PY4D21
SA090111nHTP_5neg_D21_1-71-6RUQD21
SA090112nHTP_5neg_D21_1-69-7PTFD21
SA090113nHTP_5neg_D21_1-67-6MX8D21
SA090114nHTP_5neg_D21_1-65-7VN0D21
SA090115nHTP_5neg_D21_1-72-4PGJD21
SA090116nHTP_5neg_D21_1-74-7KCKD21
SA090117nHTP_5neg_D21_1-78-6ULAD21
SA090118nHTP_5neg_D21_1-79-4UE4D21
SA090119nHTP_5neg_D21_1-77-9AYBD21
SA090120nHTP_5neg_D21_1-76-3XMZD21
SA090121nHTP_5neg_D21_1-60-0YGGD21
SA090122nHTP_5neg_D21_1-73-1BX5D21
SA090123nHTP_5neg_D21_1-52-6YZKD21
SA090124nHTP_5neg_D21_1-7-6CNND21
SA090125nHTP_5neg_D21_1-9-5BBHD21
SA090126nHTP_5neg_D21_1-4-8UHCD21
SA090127nHTP_5neg_D21_1-3-4UDCD21
SA090128nHTP_5neg_D21_1-2-3MZXD21
SA090129nHTP_5neg_D21_1-10-3TMLD21
SA090130nHTP_5neg_D21_1-11-3UU4D21
SA090131nHTP_5neg_D21_1-51-2MT7D21
SA090132nHTP_5neg_D21_1-83-2BDXD21
SA090133nHTP_5neg_D21_1-47-2AMQD21
SA090134nHTP_5neg_D21_1-15-0REDD21
SA090135nHTP_5neg_D21_1-13-2AYDD21
SA090136nHTP_5neg_D21_1-55-5CHYD21
SA090137nHTP_5neg_D21_1-84-4UWUD21
SA090138nHTP_5neg_D21_2-11-4ZCAD21
SA090139nHTP_5neg_D21_2-12-6LKLD21
SA090140nHTP_5neg_D21_2-10-2JALD21
SA090141nHTP_5neg_D21_2-9-8HZ9D21
SA090142nHTP_5neg_D21_2-8-3XHTD21
SA090143nHTP_5neg_D21_2-13-0CYLD21
SA090144nHTP_5neg_D21_2-16-5MH0D21
SA090145nHTP_5neg_D21_1-3CMMD21
SA090146nHTP_5neg_D21_3-8FHCD21
SA090147nHTP_5neg_D21_2-20-2YMYD21
SA090148nHTP_5neg_D21_2-19-4VEED21
SA090149nHTP_5neg_D21_2-18-0GGND21
SA090150nHTP_5neg_D21_2-7-9JX3D21
SA090151nHTP_5neg_D21_2-6-8XWPD21
SA090152nHTP_5neg_D21_1-88-0HF9D21
SA090153nHTP_5neg_D21_1-89-7GXDD21
SA090154nHTP_5neg_D21_1-87-8AF8D21
SA090155nHTP_5neg_D21_1-86-2RHED21
SA090156nHTP_5neg_D21_1-85-0KM5D21
SA090157nHTP_5neg_D21_1-93-1NRTD21
SA090158nHTP_5neg_D21_1-94-1UJ7D21
SA090159nHTP_5neg_D21_2-3-5KPVD21
SA090160nHTP_5neg_D21_2-2-5NL0D21
SA090161nHTP_5neg_D21_2-1-2GGND21
SA090162nHTP_5neg_D21_1-95-8GZFD21
SA090163nHTP_5pos_D21_1-1-9BN7D21
SA090164nHTP_5neg_D21_1-1-9BN7D21
SA090165nHTP_5pos_D21_1-95-8GZFD21
SA090166nHTP_5pos_D21_1-94-1UJ7D21
SA090167nHTP_5pos_D21_2-1-2GGND21
SA090168nHTP_5pos_D21_2-2-5NL0D21
SA090169nHTP_5pos_D21_2-3-5KPVD21
SA090170nHTP_5pos_D21_1-93-1NRTD21
SA090171nHTP_5pos_D21_1-89-7GXDD21
SA090172nHTP_5pos_D21_1-85-0KM5D21
SA090173nHTP_5pos_D21_1-84-4UWUD21
SA090174nHTP_5pos_D21_1-86-2RHED21
SA090175nHTP_5pos_D21_1-87-8AF8D21
SA090176nHTP_5pos_D21_1-88-0HF9D21
SA090177nHTP_5pos_D21_2-6-8XWPD21
SA090178nHTP_5pos_D21_2-7-9JX3D21
SA090179nHTP_5pos_D21_2-18-0GGND21
SA090180nHTP_5pos_D21_2-16-5MH0D21
SA090181nHTP_5pos_D21_2-19-4VEED21
SA090182nHTP_5pos_D21_2-20-2YMYD21
SA090183nHTP_5pos_D21_1-3CMMD21
SA090184nHTP_5pos_D21_2-13-0CYLD21
SA090185nHTP_5pos_D21_2-12-6LKLD21
SA090186nHTP_5pos_D21_2-8-3XHTD21
SA090187nHTP_5pos_D21_2-9-8HZ9D21
SA090188nHTP_5pos_D21_2-10-2JALD21
SA090189nHTP_5pos_D21_2-11-4ZCAD21
SA090190nHTP_5pos_D21_1-79-4UE4D21
SA090191nHTP_5pos_D21_1-78-6ULAD21
SA090192nHTP_5pos_D21_1-13-2AYDD21
SA090193nHTP_5pos_D21_1-11-3UU4D21
SA090194nHTP_5pos_D21_1-15-0REDD21
SA090195nHTP_5pos_D21_1-47-2AMQD21
SA090196nHTP_5pos_D21_1-51-2MT7D21
SA090197nHTP_5pos_D21_1-10-3TMLD21
SA090198nHTP_5pos_D21_1-9-5BBHD21
SA090199nHTP_5pos_D21_1-2-3MZXD21
SA090200nHTP_5pos_D21_1-3-4UDCD21
SA090201nHTP_5pos_D21_1-4-8UHCD21
SA090202nHTP_5pos_D21_1-7-6CNND21
SA090203nHTP_5pos_D21_1-52-6YZKD21
SA090204nHTP_5pos_D21_1-55-5CHYD21
SA090205nHTP_5pos_D21_1-73-1BX5D21
SA090206nHTP_5pos_D21_1-72-4PGJD21
SA090207nHTP_5pos_D21_1-74-7KCKD21
SA090208nHTP_5pos_D21_1-76-3XMZD21
SA090209nHTP_5pos_D21_1-77-9AYBD21
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Collection:

Collection ID:CO001303
Collection Summary:All human subjects in this study were consented according to Colorado Multiple Institutional Review Board (COMIRB)-approved protocols. Written informed consent was obtained from parents or guardians of participants under the age of 18, and assent was obtained from participants over the age of 7 who were cognitively able to assent. Deidentified plasma samples for Cohort 1 were obtained from the Translational Nexus Clinical Data Registry and Biobank (University of Colorado Anschutz Medical Campus, COMIRB 08-1276). Additional plasma and WBC samples were obtained through the Crnic’s Institute Human Trisome Project (University of Colorado Anschutz Medical Campus, COMIRB 15-2170, www.trisome.org). Plasma was collected in Vacutainer tubes (EDTA–purple capped or Lithium heparin–light green capped) and stored at -80°C. Participant medical history was collected by the respective biobanks.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR001324
Treatment Summary:N/A

Sample Preparation:

Sampleprep ID:SP001317
Sampleprep Summary:For plasma analyses, a volume of 20μL of was extracted in 480μL of ice-cold methanol:acetonitrile:water (5:3:2). For CSF analyses, a volume of 20μL was extracted in 180μL and for cell-based experiments, 2 million cells were extracted in 1mL of the same ice-cold lysis solution. Subsequently, these solutions were vortexed for 30 minutes at 4°C. Insoluble proteins were pelleted by centrifugation (10 minutes at 4°C and 12,000 g) and supernatants were collected and stored at -80°C until analysis. For quantitative analysis of kynurenine pathway (KP) metabolites, supernatants were spun in a Speedvac until dry and resuspended in 0.1% formic acid in water as previously described (PMID: 30213797, 30143553).

Combined analysis:

Analysis ID AN002061 AN002062
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Vanquish Thermo Vanquish
Column Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um) Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap
Ion Mode POSITIVE NEGATIVE
Units relative abundance relative abundance

Chromatography:

Chromatography ID:CH001499
Chromatography Summary:UHPLC-MS metabolomics analyses were performed using a Vanquish UHPLC system coupled online to a Q Exactive mass spectrometer (Thermo Fisher, Bremen, Germany). 20uL of supernatant was injected for plasma and CSF samples, and 10uL of supernatant was injected for cell samples. Samples were resolved over a Kinetex C18 column (2.1x150 mm, 1.7μm; Phenomenex, Torrance, CA, USA) at 45°C using a 5-minute gradient at 450μL/minute from 5-95% B (A: water/0.1% formic acid; B: acetonitrile/0.1% formic acid) for positive mode. To monitor possible technical variability, aliquots of each of the individual samples were combined to make technical replicates, which were run after every 15 samples. Additionally, in each experiment, several lysis solution aliquots were run as blanks for artifact identification.
Methods Filename:5MMpos_method.pdf
Instrument Name:Thermo Vanquish
Column Name:Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um)
Column Temperature:45
Flow Gradient:5-95% B
Flow Rate:450uL/min
Solvent A:water, 0.1% formic acid
Solvent B:acetonitrile, 0.1% formic acid
Analytical Time:5min
Chromatography Type:Reversed phase
  
Chromatography ID:CH001500
Chromatography Summary:UHPLC-MS metabolomics analyses were performed using a Vanquish UHPLC system coupled online to a Q Exactive mass spectrometer (Thermo Fisher, Bremen, Germany). 20uL of supernatant was injected for each sample. Samples were resolved over a Kinetex C18 column (2.1x150 mm, 1.7μm; Phenomenex, Torrance, CA, USA) at 45°C using a 5-minute gradient at 450μL/minute from 0-100% B (A: 95% water/5% acetonitrile, 1mM NH4OAc; B: 95% acetonitrile/5% water, 1mM NH4OAc) for negative mode. To monitor possible technical variability, aliquots of each of the individual samples were combined to make technical replicates, which were run after every 15 samples. Additionally, in each experiment, several lysis solution aliquots were run as blanks for artifact identification.
Methods Filename:5MMneg_method.pdf
Instrument Name:Thermo Vanquish
Column Name:Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um)
Column Temperature:45
Flow Gradient:0-100% B
Flow Rate:450uL/min
Solvent A:95% water/5% acetonitrile, 1mM NH4OAc
Solvent B:95% acetonitrile/5% water, 1mM NH4OAc
Analytical Time:5min
Chromatography Type:Reversed phase

MS:

MS ID:MS001912
Analysis ID:AN002061
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:The Q Exactive mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) was operated in positive ion mode using electrospray ionization, scanning in Full MS mode (1μscan) from 65 to 975 m/z at 70,000 resolution, with 4 kV spray voltage, 45 sheath gas, 15 auxiliary gas. MS analysis and data elaboration were performed as described74,75. Calibration was performed prior to analysis using the PierceTM Positive Ion Calibration Solution (Thermo Fisher Scientific).
Ion Mode:POSITIVE
  
MS ID:MS001913
Analysis ID:AN002062
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:The Q Exactive mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) was operated in negative ion mode using electrospray ionization, scanning in Full MS mode (1μscan) from 65 to 975 m/z at 70,000 resolution, with 4 kV spray voltage, 45 sheath gas, 15 auxiliary gas. MS analysis and data elaboration were performed as described74,75. Calibration was performed prior to analysis using the PierceTM Negative Ion Calibration Solution (Thermo Fisher Scientific).
Ion Mode:NEGATIVE
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